The proposal describes a five-year mentored training experience designed to lead to an independent academic career in patient-oriented translational research. The applicant holds an M.D. degree and has research experience in genetics, cell and molecular biology. He is at present completing a clinical fellowship in medical genetics. Baylor College of Medicine (BCM) has a strong record of research and career development activities, and a combination of world-class clinical and basic scientific opportunities and facilities. The mentor is a renowned researcher in the field of medical genetics, with expertise in genetics of complex traits. The members of the advisory committee have been carefully selected to provide expertise in key aspects of the proposed research project, as well as career guidance for the applicant. The research proposal is patient- oriented, as it will be conducted on humans and involves direct contact between the investigator and the research subjects. It is complemented by directly-related laboratory research, providing an opportunity for a career development experience in translational medicine. The goal of the project is to understand how differences in human DNA may help explain why individuals respond differently to influenza vaccines. The research plan involves vaccination of healthy human volunteers against influenza and a combination of genome-wide genotyping, global gene expression measurements and immunophenotyping to dissect the DNA variants that influence the human immune response to the vaccine. The specific aims of the project include identification of candidate DNA regions in males and females by expression quantitative trait locus (eQTL) mapping, detailed examination of the candidate regions using fine-mapping techniques, validation of the findings in large groups of individuals, and studies to define the function of the identified DNA variants. This set of novel DNA mapping techniques has never been applied to the study of human response to vaccines before. A better understanding of the genetic variants responsible for differences in the human immune response to vaccines can lead to the development of better vaccines and adjuvants. It can also lead to accurate predictions regarding the likelihood of an adequate vaccine response or of an adverse event, thus leading to a personalized, more effective and safer approach to vaccine administration. Because the vaccines being used today are derived from microorganisms, understanding the genetic determinants of the human immune response to vaccines can also advance our knowledge of the nature of genetic control of the immune response to infection. The proposal and its career development plan will provide the applicant with training in new technologies in human genetics and in the bioinformatic and biostatistic tools that are required for the analysis of large-scale genomic data. This period of mentored training in scientific planning, implementation and communication will complement the applicant's continued development as a clinician, leading to an independent research program and a long-term career as a physician-scientist. The project looks for differences in human DNA that may help explain why individuals respond differently to influenza vaccines. Researchers use a novel approach that combines vaccination of healthy volunteers with studies of their immune response and genetic information. The results of this research will help in the development of better vaccines and allow healthcare practitioners to use a more personalized approach to vaccination.